HLA-DR antigens render interleukin-2-producer T lymphocytes sensitive to interleukin-1

Monoclonal anti-HLA-DR antibodies inhibited the production of interleukin-2 (IL-2) when added from the initiation of autologous (AMLR) and allogeneic (MLR) mixed lymphocyte reactions, but not 60 h later. The inhibitory activity of the anti-DR sera became apparent 8 h after initiation of the cultures and was maintained throughout the culture period. Interleukin-1 (IL-1) added to cultures carried out in the absence of the anti-DR antibodies significantly enhanced the production of IL-2, whereas addition of IL-1 to anti-DR-treated AMLR and MLR cultures did not restore or increase the synthesis of IL-2. However, when the anti-DR antibodies were added to IL-1-supplemented AMLR and MLR cultures 60 h or more after initiation of the reactions, the antiserum no longer inhibited the capacity of IL-1 to promote the synthesis of IL-2 or the production of IL-2. Finally, resting T cells were unresponsive to IL-1 and did not produce IL-2. It thus seemed that the anit-DR antibodies inhibited production of IL-2 in AMLR and MLR by rendering the IL-2 producer T cells unresponsive to IL-1. Cyclosporin-A, a drug that abrogates activation of T cells by blocking their receptors for HLA-DR antigens, also rendered IL-2 producer T cells unresponsive to IL-1 and abrogated the production of IL-2 in AMLR and MLR. Since resting T cells cells do not respond to IL-1 or produce IL-2, it is concluded that HLA-DR antigens of the stimulator cells participate in the production of IL-2 in AMLR and MLR by enabling the IL-2 producer T lymphocytes to respond to IL-1. Interleukin-1 promotes the production of IL-2 by IL-1-sensitive T cells. Once the IL-2-producer T cells become sensitive to IL-1, there is no further requirement for HLA-DR antigens.